More than 2% of the adult population of the US harbors a pancreatic cyst and the increasing use of abdominal imaging is likely to increase the diagnosis of these lesions as incidental findings. Because these cysts can either be self-limiting lesions or represent true precursors to deadly invasive adenocarcinomas, they pose a difficult clinical management problem. There are three main forms of pancreatic cystic neoplasms, serous cystic adenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). SCAs are thought to be totally benign whereas IPMNs and MCNs are often associated with an invasive component. The ultimate goal of this proposal is to develop clinically useful biomarkers that can distinguish these cyst types and alter clinical decision-making. This goal is practical now due to previous successes of this SPORE in the areas of genomic analysis, biomarker development and pancreatic cyst analysis. To achieve this goal, we propose a detailed molecular-analysis of neoplastic cells from all three main types of pancreatic cyst neoplasms (Aim #1). These molecular findings will be used to develop cyst fluid biomarkers (Aim #2). Cyst fluid was chosen as the target clinical sample because of promising preliminary results and because cyst fluid is routinely available in the clinic at critical decision points. The best biomarkers developed in Aim #2 will be correlated with clinical findings and outcomes in both a retrospective (Aim #3) and prospective (Aim #4) manner. The above studies will identify molecular changes that underlie the pathogenesis of pancreatic cyst development and should allow the development of clinically useful cyst fluid biomarkers.